The incidence of thyroid cancer is increasing yearly in the United States. Although the overall prognosis from thyroid cancer is excellent, no effective therapies exist for patients with distant metastases. The presence of capsular or vascular invasion is the most important predictor of outcome from thyroid cancer. Over the past decade, the oncogenes responsible for approximately 50% of thyroid cancers have been characterized, and all appear to cause constitutive activation of the PI3 kinase/Akt and MAP kinase pathways. We have demonstrated that levels of activated Akt (pAkt), in particular, are enhanced in the majority of thyroid cancers in the cells invading through tumor capsules or metastatic to cervical lymph nodes, and that the degree and localization of pAkt correlates with oncogene expression. Of particular interest is that the enhancement of pAkt occurs in the nucleus of the invading cells, pAkt co-localizes with the Aktl isoform, and nuclear pAkt is associated with cytosolic p27. Because of this unique association with nuclear Akt activity in thyroid cancer invasion in vivo, we questioned whether Akt activation in the nucleus might play an important role in inducing invasion in thyroid tumor cancer. Subsequent in vitro studies have demonstrated that thyroid cancer cell motility is associated with nuclear pAkt and cytosolic p27, and is dependent on Aktl and p27 expression. In an effort to define a regulatory mechanism for subcellular localization of Aktl, we identified the presence of a conserved functioning CRM-1 binding nuclear export signal (NES) in Akt 1. Mutation of the Aktl/NES disrupts CRM-1 binding and results in nuclear accumulation of Aktl with associated nuclear Akt activity. Expression of a nuclear export-deficient Aktl in Aktl-/- murine embryonic fibroblasts restores cell motility without inducing growth, in a p27 dependent manner. These data suggest that nuclear Aktl activity plays a functional role in cell motility. We now hypothesize that nuclear Aktl activity is a critical regulator of thyroid cancer cell motility and that regulation of Akt nuclear/cytoplasmic shuttling by thyroid oncogenes may be an important pathway for aggressive thyroid cancer behavior.